Process for the preparation of methylenebisphosphonic acids

ABSTRACT

The present invention concerns a novel process for the preparation of methylenebisphosphonic acids of the formula I ##STR1## wherein Q 1  and Q 2  are independently hydrogen or halogen, by hydrolyzing the corresponding methylenebisphosphonic acid tetraester of the formula ##STR2## wherein R has the meaning of a straight or branched alkyl group containing 1 to 4 carbon atoms, and Q 1  and Q 2  have the same meaning as above.

BACKGROUND OF THE INVENTION

The present invention concerns a novel process for the preparation ofmethylenebisphosphonic acids of the formula I ##STR3## wherein Q¹ and Q²are independently hydrogen or halogen, by hydrolyzing the correspondingmethylenebisphosphonic acid tetraester of the formula ##STR4## wherein Rhas the meaning of a straight or branched alkyl group containing 1 to 4carbon atoms, and Q¹ and Q² have the same meaning as above.

Prior known processes for the preparation of bisphosphonic acids byhydrolyzing the corresponding tetraesters have been based on the use ofstrong acids, such as halogen acids. Thus tetraesters, e.g. theisopropyl tetraester, have been boiled for several hours withconcentrated hydrochloric acid (c.f. BE-patent 672205, example VI (B)).In the publication Houben-Weyl, Methoden der Organischen Chemie, XII, 1,352-356, the hydrolysis of tetraesters with half-concentratedhydrochloric acid under elevated pressure and at 130°-145° C. isdescribed. A disadvantage with these known processes is the impurity ofthe products obtained and the numerous purification steps needed toremove byproducts and excess acid. In addition, the processes areconnected with substantial corrosion problems. From the EP-patentapplication 0200980 is known a process according to whichmethylenebisphosphonic acids have been prepared by hydrolysingtetraesters with plain water, by boiling at reflux temperature of thereaction mixture. In this case the above mentioned problems ofimpurities and corrosion are largely overcome, but another problem isthe very long reaction time, which may be as long as 16 hours, which isdisadvantageous, i.a. from the viewpoint of production economics.

SUMMARY OF THE INVENTION

Now a process has been invented for the preparation of the abovementioned methylenebisphosphonic acids and their salts according to theformula I, with a good yield and in a very pure form, whereby thecorrosion problems caused by the use of a strong acid are avoided. Bymeans of the process according to the invention it has also beenpossible to shorten the reaction time even up to one quarter or more ascompared to the process known from the EP-patent application 0200980.

The process according to the invention is thus characterized in that thehydrolysis is performed in an aqueous solution of the tetraester andhydrochloric acid, which solution contains from 1.0 to 5% by weight ofHCl, based on the whole mixture. Below the said limit the hydrolysisproceeds too slowly from a practical viewpoint and above the said limitno substantial rate increase is achieved in relation to the amount ofchloride ions added to the mixture.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph of the yield of hydrolysis (mole percent free acid)versus reaction time in hours, of three hydrolysis mixtures of thisinvention compared to plain water according to the prior art.

DETAILED DESCRIPTION

The hydrolysis is advantageously performed by boiling the aqueoussolution of the tetraester and hydrochloric acid at reflux temperature.Thus the reaction mixture contains an excess Of water with regard to thestochiometric amount of water necessary for the complete hydrolysis ofthe tetraester. This excess of water is not critical and thus a multipleexcess with regard to the stochiometric amount may be used. A practicalvolumetric amount of aqueous hydrochloric acid solution from theviewpoint of carrying out the hydrolysis is approximately 6 to 7 timesthe weight of the tetraester, whereby, on the one hand, a sufficientdegree of dissolution of the tetraester in the aqueous medium isobtained, but at the same time the difficulties caused by the increasein volume in the subsequent hydrolysis stage are avoided.

According to one advantageous embodiment the amount of hydrochloric acidin the mixture is approximately 2.5 to 5% by weight, whereby an optimalresult from the viewpoint of byproduct formation and reaction time isachieved.

The free tetraacid obtained as a result of the hydrolysis may, ifdesired, be converted to its salt, also its partial salt, in a per seknown manner by using a suitable organic or inorganic base, for examplealkali or alkaline earth metal hydroxides, carbonates or hydrogencarbonates. The salt formation may take place either after the isolationof the acid or by adding the desired base directly to the reactionmixture after the hydrolysis, without isolating the free acid.

The following example illustrates the invention.

EXAMPLE 1 Dichloromethylenebisphosphonic acid disodiumtetrahydrate

Into a three-necked flask equipped with a thermometer, a stirrer and areflux condenser, 420 ml of a 3% hydrochloric acid solution and 65 g oftetraisopropyl dichloromethylenebisphosphonate are added. TheHCl-concentration of the reaction mixture is then approximately 2.6% byweight of HCl. The mixture is boiled under reflux and the progress ofthe hydrolysis is followed by determining the concentration of the acidformed in the solution by ³¹ P-NMR. The solution is cooled to 20° to 25°C. and is treated with activated carbon. To the solution a calculatedamount of a sodium hydroxide solution is added until the pH is 3.2. Thesolution is concentrated and cooled, whereby the disodiumtetrahydratesalt of dichloromethylenebisphosphonic acid crystallizes. The crystalsare filtered and dried, whereby appr. 50 g of the product is obtained,purity >99%.

By performing the hydrolysis as described above but by using instead ofthe 3% hydrochloric acid solution, aqueous hydrochloric acid solutionsof varying strength, the hydrolysis results shown in the appendeddrawing were obtained. Next to each curve on the one hand the acidstrength of the hydrolysis mixture, and on the other hand, inparenthesis, the acid strength of the aqueous hydrochloric acid solutionused, are indicated. In the drawing the yield of hydrolysis (mol-% freeacid) are indicated as a function of reaction time, and as comparison,hydrolysis with plain water according to the EP-patent application0200980 is used. As is seen from the drawing, complete yields areobtained with the process according to the invention, by using catalyticamounts of hydrochloric acid, in a substantially shorter reaction timeas compared to the process according to the said EP-patent application.

We claim:
 1. A process for the preparation of methylenebisphosphonicacids of the formula I ##STR5## wherein Q¹ and Q² are independentlyhydrogen or halogen, consisting essentially of hydrolyzing thecorresponding methylenebisphosphonic acid tetraester having the formulaII ##STR6## wherein R is selected from the group consisting of straightand branched alkyl groups of 1 to 4 to carbon atoms and Q¹ and Q² areindependently selected from the group consisting of hydrogen andhalogen, wherein the hydrolysis is performed in a hydrolysis mixture ofthe tetraester and an aqueous hydrochloric acid solution, which mixturecontains 1.0 to 5% by weight of hydrochloric acid.
 2. The process ofclaim 1, further comprising converting the free tetraacid obtained to asalt with a base.
 3. The process of claim 1, wherein a 6 to 7-foldvolumetric amount of an aqueous hydrochloric acid solution is usedcompared to the weight of the tetraester.
 4. The process of claim 1,wherein the hydrolysis is performed by boiling at the reflux temperatureof the mixture.
 5. The process of claims 6 2, 3, or 4, wherein thehydrolysis mixture contains 2.5 to 5% by weight of hydrochloric acid. 6.The process of claim 1, wherein the tetraester of formula II is thetetraisopropylester of dichloromethylenebisphosphonic acid.